The cell-wide web coordinates cellular processes by directing site-specific Ca²⁺ flux across cytoplasmic nanocourses

Ca²⁺ coordinates diverse cellular processes, yet how function-specific signals arise is enigmatic. We describe a cell-wide network of distinct cytoplasmic nano courses with the nucleus at its centre, demarcated by sarcoplasmic reticulum (SR) junctions (≤400 nm across) that restrict Ca²⁺ diffusion and by nanocourse-specific Ca²⁺-pumps that facilitate signal segregation. Ryanodine receptor subtype 1 (RyR1) supports relaxation of arterial myocytes by unloading Ca²⁺ into peripheral nanocourses delimited by plasmalemma-SR junctions, fed by sarco/endoplasmic reticulum Ca²⁺ ATPase 2b (SERCA2b). Conversely, stimulus-specified increases in Ca²⁺ flux through RyR2/3 clusters selects for rapid propagation of Ca2+ signals throughout deeper extra perinuclear nanocourses and thus myocyte contraction. Nuclear envelope invaginations incorporating SERCA1 in their outer nuclear membranes demarcate further diverse networks of cytoplasmic nano courses that receive Ca²⁺ signals through discrete RyR1 clusters, impacting gene expression through epigenetic marks segregated by their associated invaginations. Critically, this circuit is not hardwired and remodels for different outputs during cell proliferation.